Novel Roles of Gastrin and Cholecystokinin in Islet Beta Cell Proliferation

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2007-06-12

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Presley, Brent Kevin

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Abstract

Type 1 diabetes and the latter stages of Type 2 diabetes share a common theme: an insufficient beta cell mass to maintain glucose homeostasis. In Type 1 diabetes this deficiency arises from autoimmune destruction of the beta cells. In the latter stages of Type 2 diabetes, there is a precipitous drop in beta cell mass, resulting from the combination of several factors. In the last decade, islet transplantation has re-emerged as a viable option for the treatment of Type 1 diabetes, thanks to greatly improved islet isolation protocols and immunosuppressive regimens. Despite these advancements, the supply of available islet beta cells for transplantation is greatly eclipsed by the demand. Consequently, the identification of genes or external factors that promote beta cell proliferation and survival is a key step toward developing a replenishable population of beta cells that can be used for transplantation for Type 1 diabetes. Additionally, any method discovered to promote beta cell growth or enhance beta cell function is directly applicable in the treatment of Type 2 diabetes. Through a broad-based microarray screen, the preprogastrin gene was found to be differentially expressed in our model of beta cell cytokine resistance, the INS-1res cell lines compared to unselected INS-1 cells. As a result of this finding, preprogastrin was initially evaluated for its involvement in cytokine resistance and beta cell survival. During the course of this analysis, preprogastrin was determined to exhibit significant mitogenic properties when overexpressed in INS-1 cell lines and isolated rat islets. These results led to the discovery that the related protein, preprocholecystokinin, also promotes impressive beta cell growth, in addition to enhanced beta cell function, as measured by improved glucose-stimulated insulin secretion. Several additional experiments suggest that traditional plasma membrane receptors and signaling pathways for gastrin and cholecystokinin do not explain the effect of overexpression of these prohormones on islet replication, including a lack of effect of exogenously added gastrin and cholecystokinin peptides. These results could be attributable to an intracrine mode of signaling that will require further investigation as a possible therapeutic target for the treatment of Type 1 and Type 2 diabetes.

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